Data from cultured cells have suggested that cAMP and cGMP may be important determinants of cell growth and transformation. However, few studies have examined cyclic nucleotide content and metabolism in naturally occurring tumors of man. Accordingly, in the present study we compared cAMP and cGMP levels and metabolism in carcinomas of the human colon to those of the adjacent uninvolved mucosa following therapeutic resection of these tissues. The cAMP content of the tumors, determined in samples frozen 30 min after excision, was signficantly lower than that of the adjacent mucosa, when expressed on the basis of tissue wet weight, protein or DNA content. By contrast, the cGMP content of the tumors was higher than that of the surrounding mucosa if calculated on the basis of tissue wet weight, but this difference did not persist when correction was made for the higher protein or DNA content of the tumors. Incubation of slices of mucosa or tumors with or without theophylline in vitro increased tissue cAMP and cGMP content above levels observed in frozen samples of the same tissue. However, after such incubation cAMP levels in the tumors remained clearly below that of the mucosa, while cGMP content of the two tissues did not differ. The failure of therophylline to abolish differences in cAMP content and the comparable activities of high and low Km cAMP-phosphodiesterase in homogenates of the two tissues suggested that the low cAMP content of the tumors was a consequence of diminished cAMP synthesis rather thatn enhanced degradation. This possibility was supported by the reduction in basal and maximal prostaglandin E1 (PGE1)-responsive adenylate cyclase activity found in tumor homogenates relative to those of mucosa, and the lower levels of cAMP in tumor slices following incubation of te tissues with a maximal dose of PGE1 and theophylline. The role of reduced activity of the adenylate cyclase cAMP system and/or reduced tissue cAMP/cGMP ratios in the pathogenesis of colonic carcinoma is uncertain, but these changes might favor unregulated cellular proliferation. BIBLIOGRAPHI REFERENECES: DeRubertis, F.R., R. Cayoth and J.B. Field. 1975. Reduced cAMP in Carcinoma of the Human Colon. Clin Res. 23: 337A.